Process of preparing pyrazines



Patented Aug. 22, 1950 UNITED STATES PATENT OFFICE No Drawing. Application May 28, 1948, Serial No. 29,959

11 Claims.

My invention relates to a novel synthesis of organic compounds, and more particularly to a synthesis of hydroxypyrazines.

Heretofore, the synthesis of pyrazines has been difficult of accomplishment. The methods avai1- able to the art with few exceptions have yielded the desired pyrazine compounds only in poor yields and by laborious procedures. Many attempts have been made to overcome the difliculties inherent in the processes of the prior art and to provide a suitable method of synthesis of hydroxypyrazine compounds which, because of their utility in connection with theoretical and practical chemistry, and their ready convertibility into other pyrazine compounds, are of considerable importance.

An object of my invention is to provide a simple process for the preparation of hydroxypyrazines. Another object is to provide a method of synthesizing intermediates useful in the synthesis of important organic compounds, for example, folic acid and the like. Other objects will be apparent from the following description of my invention.

In the accomplishment of the above and other objects, I have discovered that hydroxypyrazines can be obtained in excellent yield by condensing 1.2-dicarbonyl compounds With a-aminocarboxylic acid amides.

A preferred manner of carrying out the process of my invention is as follows: Approximately molar-equiva ents of the 1,2-dicarbonyl compound and the a-am no acid amide are dispersed in a solvent. The mixture is cooled to about C. and to it is added with stirring a solution contained about a molar-e uivalent of an alkali or base having a dissociation constant of at least about 1 10". Condensation of the dicarbonyl compound and the amide occurs and a subst tuted hydroxypyrazine is produced.

Isolation of the hydroxypyrazine from the reaction mixture is efiected by neutralizing the reaction mixture with an acid and separating, as by filtration, the hydroxypyrazine which frequently is insoluble in the neutralized reaction mixture and so precipitates. Alternatively, in case the hydroxypyrazine is quite soluble in the neutralized reaction mixture, the neutral mixture is evaporated to dryness, preferably in vacuo, and the hydroxypyrazine is separated by extraction with and subsecuent evaporation of an organic solvent in which the hydroxypyrazine is selec tively soluble. Additional alternative isolation procedures will be apparent to those skilled in 2 l the art. The hydroxypyrazine which is isolated is purified by conventional means, for example, by recrystallization from one or more solvents;

The following equation showing the formation of 2-hydroxy-5,6-dimethylpyrazine from diacetyl and glycine amide is given for the purpose of illustrating the reaction involved in the preparation of hydroxypyrazine compounds in accordance with my invention:

1,2-dicarbonyl compounds which may be em ployed in my invention include 1,2-diketone and a-ketoaldehydes. Illustrative examples of suitable dicarbonyl compounds are glyoxal, methylglyoxal, ethylglyoxal, diacetyl, diethylglyoxal, propylglyoxal, dipropylglyoxal, phenylglyoxal, benzil, dibenzylglyoxal, o-benzoquinone, and 1,2- diketocyclohexane. It will be apparent from the above-mentioned compounds that both aliphatic and aromatic dicarbonyl compounds may be used in carrying out my invention.

Many a-amino acid amides are suitable for use in my invention, illustrative examples of which are glycine amide, alanine amide, tyrosine amide, uz-ElllllllO-Il-blltYliO acid amide, methionine amide, aspartic acid amide, aminomalonamide, a-aminophenylacetamide, threonine amide, valine amide, tryptophane amide, phenylalanine amide, and. the like. The preparation of the amino acid amides conveniently is carried out according to the procedure of Konigs and Mylo, disclosed in Ber. 41, 4427 (1908).

As noted above in the description of the preferred manner of carrying out my invention a base, i. e. an alkaline material, is employed for eiTecting the condensation of the 1,2-dicarbonyl compound and the a-amino acid amide. Suitable bases are those having a dissociation constant of about 1X10" or greater. Organic bases may be used, such bases including basic nitrogen compounds, of which examples are piperidine, di-

ethylamine, triethylamine, ethylamine, methylamine, secondary butylamine and the like. As will be understood by those skilled in the art, organic bases which will react with the 1,2-dicarbonyl compound are not desirable since the reaction between the chosen base and the 1,2-

, dicarbonyl compound reduces the amount of 1,2-

In practice, however, it is often observed that production of one isomer to the substantial ex- 65 dicarbonyl compound available for the desired reaction, and moreover the presence of the unwanted Icy-product interferes with the formation and isolation of the desired reaction product. Alternatively, inorganic bases and basic salts having a dissociation constant of at least about 1 1(lmay be employed as condensing agents. Satisfactory inorganic basic compounds include? metal hydroxides; metal carbonates, metal bi carbonates and the like.

It should be noted that various iii-aminocarboxylic acid amides are in:themselves--suifi-iciently basic to cause their condensation with a 1,2-dicarbonyl compound to prooeeddn a-satis-i factory manner so that no-added base is-nec'essary. Such is the case, for example, with aminomalonamide which will react readily -witl1"1,2.-'- dlcarbonyl compounds of the nature of cliacetyli to produce th hydroxypyrazine.

The function of the. base in promoting the '20 desired reaction between the 1,2-dicarbonyl compound-and the a-amino acid amide is notunderstood, but-the presence ofa sufficient amount of basic material to produce an alkaline reaction mixtureappearsto be necessary for the initiation and completion of the'condensation reaction. The reaction may be carried out byusing an amountrof base lessthan the stoichiometric or equivalent amount, and the desired pyrazine compound will be produced 'ingoodyield. However, in general it is preferable to employ a molecularly equivalent amount of the base since the use of an equivalent amount is;productiv.e.of higher yields of the pyrazine'compotmd.

The solventwhich is employed as a'dispersant of the reagents used in the preparation of the hydroxypyrazine may be any of numerous solvents. The solvent must, of course, be an'inert solventythat is; one which will not take part'in the reaction. It is desirable to employ a solvent 40 which possesses a substantial solubility for all the reagents involved in the reaction, but the productionof the hydroxypyrazinemay be accomplished with but slight decrease in yield even though one or more of the reagents has only a slight solubility in the seleoted'solvent. Of the numerous 'solventswhich may be employed, illustrative examples'arewater; monobasic alcohols, such as' methanol, ethanol, butanol, hexa-nol and the 'like; polybasic alcohols, such as ethyiene- 5 glycol, ,propyleneglycol; hydrocarbons, such as benzene'and toluene; and chlorinated hydrocarbons, such as chloroform, ethylene dichloride and carbon tetrachloride. Additional suitable solvents'will be suggested by the above-mentioned examples.

It will be apparent that when using unsymmetrical 1,2-diketones and ketoaldehydes in my novel process, there may be produced a mixture of two isomeric hydroxypyrazines. ample, reaction ofralanine amide with methylglyoxal may give rise to 3,5-dimethyl-2-hydroxypyrazine and 3,6-dimethyl-2 hydroxypyrazine. the

clusion of the other isomer occurs. Thus, for example, condensation of methylglyoxal with aminomalonamide yields only 2-hydroxy3-carboxamido-6-"nethylpyrazine. In case a mixture of isomersresults, the mixture may be separated into its components by known'methods of fractional' crystallization, selective elution and the like.

The condensation of the 1,2-dicarbonyl compound and the a-amino acid amide generally is Thus, for ex- 60 carried out at a temperature below room temperature to avoid too rapid a reaction and the consequent formation of tarry products. A temperature below 0 C. is usually desirable, and preferably the temperature at which the reactants are mixed is about 10 to about 30 C. After mixing the reactants at a low temperaturenthe' reaction mixture-is allowed ito rise to roomtemperature slowlyduring which time the condensation of the reactants is substantially completed. However, higher reaction temperaturesrmay' beemployed When the 1,2-dlcarbonyl compound used in the reaction is one which contains-carbonylgroups of relatively low activity as is -the-case-',-"for example, with diaryl diketones such asbenzil, and sterically hindered carbonyl compounds. vIn-such cases temperatures as high as:100 are not only satisfactory but are desirable in order to reduce the period of time required for'the condensation to take place.

The following specific examples will serve to illustratethe practicewof myinvention;

EXAMPLE. 1

Preparation of'2 hydrory-3-carbo:camidopymzine 2- hydroxy-3-carboxamidopyrazlne. represented by. theformulamay beprepared .as. follows 1..

25.g..(0.166 mol). ofAO percentaqueousglyoxal solution. are diluted with 25ml. of water, and 11.7 g. (0.10 mol) of finely powdered.aminomalonamide are added... The resulting mixture is..cooled..to. about .15 C..by. means 0f.an.icesalt-.mixture and. 10 .ml.. (0.125. mol) of 12.5. N sodiumhydroxide solution. are added dropwise with. stirring, the. temperature. of the reaction mixture beingkept below-10 C. Tnemixture is..a1lowed.; to. stand..=at..-room. temperature for about 2 hours during which time the reaction is completed .and .a .crystalline. precipitate comprising;. the. sodium .salt .of, Z-hydroxy-S-carboxamidopyrazineseparates. 10 I111. of. glacial acetic acid are addedwithstirring and theresulting precipitate of 2-hydroxy-3-carboxainidopyrazine is.filtered off, washedwith water. andacetone and dried. 2.-hydroxy-3-carboxamid'opyrazine is obtained in a yield of about 12.5 g.,, or percent of. theory.v After recrystallization from water it melts withdecomposition at about 265. C.

EXAMPLE 2 Preparation'of Z-hydroxy-3-0arboocamidop razine 2-hydroxy-3-carboxamido'pyrazine may also be prepared as follows:

9.86 g. (1.7 mol) of solid glyoxal polymer are dssolved' in 50 ml. of methanol, and 11.7'g. (0.10 mol) of aminomalonamide'areadded. The solution is cooled to about-0C. b means Of an icesalt mixture, and 12.8 ml. of diethylamine are added dropwise while stirring. After addition of the diethylamine, the'mixture is allowed to stand at room temperature for 2 'hours. 10 ml. of glacial acet c acid are'then added with stirring, and the mixture is poured into 50 ml. of cold water whereupon there is produced-a precipitate of Z-hydroxy-3-carboxamidopyrazine. The precipitate is filtered off, washed with Water and acetone, and dried;

EXAMPLE 3 Preparation of 2-hydroxy-Zi-carbahzido-Sfidimethylpyrazine "'2'-hyd1oxy- 3 -carbamido-5,6-dimethylpyrazine represented by the formula N CH3 OONHiI CH3 OH may be prepared as follows:

M 8.6 (0.10 mol) of diacetyl are dissolved in 25 ml. of ethanol and 11.7 g. (0.10 mol) of aminomalonamide are added. The solution is cooled to about C. and maintained at that temperature. To the mixture 10 ml. of 12.5 N potassium hydroxide solution are added dropwise, with stirring. The mixture is allowed to stand for 2 hours at room temperature, during which time a precipitate of the potassium salt of 2-hydroxy-3- carbamido-5,G-dimethylpyrazine separates. 10 m1. of glacial acetic acid are added to convert the salt to the free phenol, i. e. 2-hydroxy-3carbamido-5,6-dimethylpyrazine. The 2-hydroxy-3- carbamido-5,6-dimethylpyrazine ls filtered ofi, washed with water, and dried. It is obtained in a yield of about 93 percent of theory. Upon recrystallization from pyridine it melts with decomposition at about 231-232 C.

EXAMPLE 4 7 Preparation of 2-hydroscg/-5-methylpymzine Z-hydroxy-S-methylpyrazine represented by the formula OH N may be prepared as follows:

To a solution of 8.8 g. of glycine amide in 50 ml. of methanol cooled to about 80 C. is added a similarly cooled solution of 7.2 g. of methyl glyoxal in 25 ml. of methanol. To the mixture maintained at a temperature below about -10 C. are

added, dropwise and with stirring, 10 ml. or" 12.5

N aqueous sodium hydroxide solution. The temperature of the reaction mixture is held at C. ior 2 hours, and the mixture is then permitted to rise'to room temperature and is there maintained for a further period of 3 hours. ml. of 12 N hydrochloric acid are added to the mixture to neutralize the sodium hydroxide and 5 g. of solid sodium bicarbonate are added to neutralize excess hydrochloric acid. The mixture is evaporated to dryness in vacuo and the resulting residue, which contains the desired 2-hydroxy-5-methylpyrazine, is extracted with three 100 ml. portions of boiling chloroform. The chloroform extracts are combined and evaporated in vacuo, leaving as a resi- 6 due 8.5 g. of 2-hydroxy-5-methylpyrazine. The 2-hydroxy-5-methylpyrazine is purified by recrystallization from ethyl acetate. About 5.2 g. (42 percent of theory) of pure 2-hydroxy-5-methylpyrazine melting at about 144-146" C. are obtained.

- EXAMPLE 6 Preparation of Z-hydroxy-3,5,6-trimethylpyraeine 2-hydroxy-3,5,6-trimethylpyrazine represented by the formula N om on:

all; \N OH is prepared from 8.6 g. of diacetyl and 10.4 g. of alanine amide according to the procedure described in Example 4 for the preparation of 2- hydroxy-5-methylpyrazine. 2-hydroxy-3,5,6-trimethylpyrazine melting at about 193-194 C. is obtained in the amount of 8.0 g. which corresponds to about 77 percent of theory.

EXAMPLE '7 Preparation of 2-hydr0xy-3-carboxamido-5,6-

diphenylpyrazine 2 hydroxy 3 carboxamido 5,6 diphenylpyrazine represented by the formula N o ONH:

\N/OH may be prepared as follows:

A mixture consisting of 11.7 g. of aminomalonamide, 21 g. of benzil and 350 ml. of percent aqueous ethanol is heated to about -70" C. and 10 ml. of 12.5 N aqueous hydroxide solution are slowly added with stirring. The reactants dissolve to form a clear brown solution in Which after standing for a few minutes there is formed a copious crystalline precipitate of the sodium salt of 2 hydroxy 3 carbamido 5,6 diphenylpyrazine. The mixture is cooled to about 10 0., the crystals are separated by filtration and washed with acetone. The crystals are suspended in 200 ml. of acetone and the suspension is treated with 20 ml. of concentrated hydrochloric acid to liberate 2 hydroxy 3 carboxamido 5,6 diphenylpyrazine as the free phenol. The resulting acetone solution is diluted with 500 ml. of water, whereupon the 2-hydroxy-3-carboxamido-5,6- diphenylpyrazine precipitates as an oil which crystallizes upon standing for a short period of time. The Z-hydroxy-S-carboxamido-5,6- diphenylpyrazine is purified by recrystallization from a mixture of acetone and petroleum ether. 23 g. of 2-hydroxy-3-carboxamido-5,6- diphenylpyrazine melting at about 174-175 C. are obtained.

EXAMPLE 8 Preparation of 2-hydro:ty-5,6-diphenylpyrazine 2 hydroxy 5,6 diphenylpyrazine represented by the formula methanolgzis ihEfi-tfidito-about 30- C; and 1m [111.10g aqueous 12.53 N sodium; carbonate solution; are added slowlygwith stirring. The mixturegisthen heated to. refluxing. temperature *for '3 orminutes. The mixture'is-cooled and neutralizedzwith about 20 ml. of concentrated hydrochloric acid wheres upon the 2 hydroxy' 5,6;.- diphenylpyrazine precipitates. It is filtered off. and purified by recrystallization from a mixture ofacetone'and' petroleumxether. 2 hydroxy 5,6 edibhenrlpyrazine melting at about 225-227"'CLiS-Obtflilliid in a yield of about 22.7 g. which corresponds to about 97 percent ortheoryb EXANIPLE 9 Preparation of Z-hydroaty-Ii-(fi-methylthioethyl) pyrazine 2 hydroxy- 3 (o methylthioethylipyrazine represented by the. formula may vbe .prepared as follows:

To'a solution of 13.4 g. of methionine amide in 50 ml. of isopropanol cooled to about 30 C. is addedia similarly cooled: solution ch55 g. of glyoxal in 50 ml. of: isopropanol. Tothis mixture maintained at a temperature-below about 10 C., 10 ml. of 12.5"Niaqueous'potassium hydroxide solution are added dropwise-with stirring. The reaction mixture is allowedto stand at 5 C. for 12 hours and then at' room temperature for a further period of 2 hours. m1. of 12 N hydrochloric acid are added to neutralize'the potassium hydroxide and 5 g. of. solid sodium bicarbonateiare addedito neutralize any excess hydrochloric acid, and the mixture is evaporated to dryness in vacuo. The residue comprising 2-hydroxy-3-(,8.m'ethylthioethybpyrazine is extracted with three 10.00 mi. portions. of boiling chloroform and the combined chloroform extractsare evaporated 'to'drynessleaving a residue comprising; 2 hydroxy-3 (B-methylthioethyl) pyrazine. The substituted. pyrazine' is purified by recrystallizing it from ethyl'acetate. 18.3 g. (97 percent of theory) of 2-hydroxy-3- (fi-methylthioethyl) pyrazine melting at about 96-97 C..are obtained;

EXAMPLE 10;

Preparation of z-hydroxy 3-phenyl-5,6- tiiinethyZ pyrazine 2 --hydroxy 3 phenyl --5,6.- dimethylpyrazine represented by the formula is'prepared from diacetyl and a-amin'ophenylacetamide according to the procedure described in Example 5.

EXAMPLEII Preparation of. Lhyd 'oxy-(i- (p-hydroxyphenyl) 5,6 -dz'methylpyrazine.

2-hydroxy-3- (p-hydroxyphenyl) -5,6-dimethylpyrazine represented'bythe formula isprepared from diacetyl and tyrosine-amide according to the procedure described in-Example '5.

EXAMPLE .12

Preparation of 2-hydromy-3-hydroxvmcthylt pyrazine 1 2-.-hydroxy.- 3 hydroxymethylpyrazine represented by the formula \N on is prepared from glyoxal' and serineamideho cording to the procedure'described in Example 5.

In the above examples, the processesemployed' have shown the addition of the baseto ami-x' ture of the dicarbonyl compound and'the amino acid amide. This order of addition is usually followed for the sake of convenience, but no pare ticular order of addition is required to produce the desi;ed reaction.

I claim:

1. The process of preparing hydroxypyrazinw which comprisesreacting a 1,2-dicarbony1 compound with. an a-aminocarboxylic acid amide;

2. The process of preparing hydroxypyrazlml which. comprises 1 condensing a 1,2-dlcarbonyl compound with an a-aminocarboxylic acid amide infthe. presence of a base having a dissociation constant of at least about 1x10 andzisolatln'g the hydroxypyrazine produced bythe condense tion.

3. The process according to claim 2 in which the-1,2-dicarbonyl compound is an-a-ketoxaldehyde.

4. The process according to claim 2 inrwhfch the 1,2+dicarbony1 compound is a 1,2-diketone:

5. The processor preparing hydroxypyzazlnes which comprises mixing a dispersion of a 1,2.-dl= carbonyl compound and an a-aminocarboxylic acidtamide in a solvent with a base having-a dis, sociation constant of at least about 1x104; neu; tralizing the reaction mixture, and isolating the hydroxypyrazine which is produced.

6. The process of preparing hydroxypyrazinel which comprises providing in acold' solutlonpa mixture of approximately equivalent amounts of a 1,2-dicarbonyl compoundan a-aminocarboxylic acid amide, and a base having a dissociation constantof at least about 1x 10- warming the mixture to about room temperature, and isolating the hydroxypyrazine which is produced.

7. The process of preparing hydroxypyrazines which comprises providing a cold solution of a 1,2-dicarbonyl compound and an a-aminocar boxylic acid amide, mixing with said cold solution a base having a. dissociation constant" greater than about 1x10, allowing the temperature of the reaction mixture to rise to about room tem:- perature, neutralizing the reaction mixture with acidand separatingthe hydroxypyrazine which is produced.

8. The process according to claim.7 in which thcbase isa metal hydroxide havinga dissociation constant greater than about 1 lO.-".'

9.. The process accordingto claim '7 in which the base is sodium hydroxide- 10..Ihe process of preparing a hydroxypyrav zine. which comprises providing adis'persion ora di-,(monccyclic arylhydrocarbon). 1,2 diketone and an a-aminocarboxylic acid amidein-aninert solvent, mixing with said dispersion a basehaving adissociationeonstant greater than. about 1. :10-", maintaining said solution at a temperature below about l00 C. until the diketoneand the. a-aminocarboxylic= acid amide have substantially completely reacted, and separating the hythe a-aminocarboxylic acid amide have substandroxypyrazine which is produced. tially completely reacted, and separating the hy- 11. The process of preparing a hydroxypyradroxypyrazine which is produced. zine which comprises providing a dispersion of a REUBEN G. JONES. di-(lower aliphatic-hydrocarbon) 1,2 diketone 5 and an aminocarboxylic acid amide in an inert REFERENCES CITED solvent, mixing with said dispersion a base hav- The f ll i references are of record in the ing a dissociation constant greater than about file of this patent;

1 10-", maintaining said solution at a temperature below about until the diketone and 10 Krems et al., Chemical Reviews, 40, 311 (1947). 

1. THE PROCESS OF PREPARING HYDROXYPYRAZINES WHICH COMPRISES REACTING A 1,2-DICARBONYL COMPOUND WITH AN A-AMINOCARBOXYLIC ACID AMIDE. 